TY - JOUR T1 - Altered Aβ Formation and Long-Term Potentiation in a Calsenilin Knock-Out JF - The Journal of Neuroscience JO - J. Neurosci. SP - 9097 LP - 9106 DO - 10.1523/JNEUROSCI.23-27-09097.2003 VL - 23 IS - 27 AU - Christina Lilliehook AU - Ozlem Bozdagi AU - Jun Yao AU - Manuel Gomez-Ramirez AU - Nikhat F. Zaidi AU - Wilma Wasco AU - Sam Gandy AU - Anthony C. Santucci AU - Vahram Haroutunian AU - George W. Huntley AU - Joseph D. Buxbaum Y1 - 2003/10/08 UR - http://www.jneurosci.org/content/23/27/9097.abstract N2 - Calsenilin has been identified as a presenilin-binding protein, a transcription factor regulating dynorphin expression, and a β-subunit of Kv4 channels and could, thus, be a multifunctional protein. To study these functions of calsenilin in vivo and to determine the neuroanatomical expression pattern of calsenilin, we generated mice with a disruption of the calsenilin gene by the targeted insertion of the β-galactosidase gene. We found that calsenilin expression (as represented by β-galactosidase activity) is very restricted but overlaps better with that of presenilins and Kv4 channels than with dynorphin, suggesting that calsenilin may regulate presenilin and Kv4 channels in brain. Aβ peptide levels are reduced in calsenilin knock-out mice, demonstrating that calsenilin affects presenilin-dependent γ-cleavage in vivo. Furthermore, long-term potentiation (LTP) in dentate gyrus of hippocampus, in which calsenilin is strongly and selectively expressed, is enhanced in calsenilin knock-out mice. This enhancement of LTP coincides with a downregulation of the Kv4 channel-dependent A-type current and can be mimicked in wild-type animals by a Kv4 channel blocker. The data presented here show that lack of calsenilin affects both Aβ formation and the A-type current. We suggest that these effects are separate events, caused by a common mechanism possibly involving protein transport. ER -